Adrenocortical stress response in children with a variety of febrile illnesses was prospectively evaluated in 76 patients presenting to a general pediatric clinic with temperature greater than 101 degrees F (38.3 degrees C). Serum cortisol concentrations at presentation and again after recovery from infection were determined. Overall mean magnitude change in cortisol concentrations was 3.6-fold. Cortisol response was unrelated to the height of temperature but significant differences depending on clinical diagnosis were identified. The largest response (5-fold) was observed in patients with pneumonia, bacterial meningitis and fever of undetermined etiology. Current recommendations to double or triple replacement hydrocortisone dosage during times of increased stress in children with adrenal insufficiency are adequate only for simple febrile illnesses such as upper respiratory infection and streptococcal pharyngitis but could be subtherapeutic for infections such as pneumonia, meningitis and fever of undetermined origin, which imply a greater systemic involvement. It is possible, but untested, that a 4- to 5-fold increase in dosage would be more appropriate in those conditions.